CA2030988C - Pharmaceutical for subcutaneous or intramuscular administration containing polypeptides - Google Patents
Pharmaceutical for subcutaneous or intramuscular administration containing polypeptides Download PDFInfo
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- CA2030988C CA2030988C CA002030988A CA2030988A CA2030988C CA 2030988 C CA2030988 C CA 2030988C CA 002030988 A CA002030988 A CA 002030988A CA 2030988 A CA2030988 A CA 2030988A CA 2030988 C CA2030988 C CA 2030988C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/18—Growth factors; Growth regulators
- A61K38/1816—Erythropoietin [EPO]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/49—Urokinase; Tissue plasminogen activator
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/55—Protease inhibitors
- A61K38/57—Protease inhibitors from animals; from humans
- A61K38/58—Protease inhibitors from animals; from humans from leeches, e.g. hirudin, eglin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Dermatology (AREA)
- Biomedical Technology (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Tropical Medicine & Parasitology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
Liquid pharmaceuticals for subcutaneous (sc) or intra-muscular (im) administration containing a polypeptide and at least one amino acid, a process for the preparation of such a pharmaceutical and the use of an amino acid, which is suitable for sc or im administration, in a solution of a polypeptide are described.
Description
Bd~HRIIdGf~TERKE d4~tTIE~iGESEULSCH~'T HOE 89/8~~044 -- I~la 790 l~r. Ha/Hd Description Pha~naceutical for subcutaneous or intramnuscular administration containing polypeptides The invention relates to a liquid pharmaceutical for subcutaneous (sc) or intramuscular (im) administration containing a polypeptide and at least one amino acid, a process for the preparation of such a pharmaceutical and the use of an amino acid, which is suitable for sc or am administration, in a solution of a polypeptide.
The presentation forms of proteins to be used therapeu-tically are with a few exceptions limited ~to intravenous administration. Oral administration of polypeptides is in many cases unsuccessful, as the polypeptides are degraded in the gastrointestinal tract. It has already been attempted with the aid of various methods, for example by micro encapsulation in liposomes, to develop orally administrable presentation forms of polypeptides. Uwtil now, however, these methods were only suitable for low molecular weight polypeptides.
It has therefore been attempted to administer the poly-peptides sc or im. However, in this case it turn s out that sc or im administration, in comparison to classical iv administration, offers a distinctly poorer bioavail-ability or can be affected by local intolerability reactions.
However, sc and im administration forms offer potentially ~0 important advantages in comparison to iv administration.
among these are included, in particular, 'the possibility of self-treatment for the patients and a longer-lasting action of 'the therapeutic.
The presentation forms of proteins to be used therapeu-tically are with a few exceptions limited ~to intravenous administration. Oral administration of polypeptides is in many cases unsuccessful, as the polypeptides are degraded in the gastrointestinal tract. It has already been attempted with the aid of various methods, for example by micro encapsulation in liposomes, to develop orally administrable presentation forms of polypeptides. Uwtil now, however, these methods were only suitable for low molecular weight polypeptides.
It has therefore been attempted to administer the poly-peptides sc or im. However, in this case it turn s out that sc or im administration, in comparison to classical iv administration, offers a distinctly poorer bioavail-ability or can be affected by local intolerability reactions.
However, sc and im administration forms offer potentially ~0 important advantages in comparison to iv administration.
among these are included, in particular, 'the possibility of self-treatment for the patients and a longer-lasting action of 'the therapeutic.
In WO 86/06962 and ~P-A-0,292,908, methods for sc ox im administration of proteins in the presence of hydxoxyl-amine ox methylamine are described. however, it is known that these substances can only be used in a restricted 6 manner owing to their limited tolerability.
The object of the present invention was therefore to make available an agent containing a polypeptide, which is suitable for sc ox im administration.
This object is achieved according to the invention in that at least one amino acid, ox a salt, derivative or homolog of an amino acid, is incorporated in the poly-peptide-containing solution. Preferably, a D- or h-amino acid is incorporated.
It has surprisingly been shown that the addition of such 15. a substance drastically improves the bioavailability and tolerability of polypeptides administered sc or im and thus makes possible their sc ox im administration.
Substances suitable for the purpose according to the invention are, for example, lysine, ornithine, arginine, diaminopimelic acid, agmatine, creatinine, guanidino-acetic acid, acetylornithine, citxulline, arginino-succinic acid, tranexamic acid or epsilon-aminoca;proic acid. A feature common to them all is the presence of a basic group in the form of an amino or guanidino group.
A particularly suitable combination has proved to be arginine and lysine, preferably 0.001 to 1 mo~./1., par-ticulaxly preferably 0.01 to 0.5 moll. The bio-availaba.lity of polypeptides administered sc or im is distinctly increased by such an addition in compaxisan to ~0 a solution which contains the polypeptide and, if de-sired, customary additives such as stabilizers.
This favorable influence of these substances on the bio-availability and/or improvement in the tolerability could be observed particularly for t-PA (tissue plasminogen activator), a t-PA mutant, hirudin, urokinase, AT III
(antithrombin III), factor ~CIIT, EFO (erythropoietin), von Willebrand factor and PP4 (placenta protein 4). The activity of the proteins to which, according to the invewtion, the described substances were added is main-tained even after lyophilization and dissolving before administration in sterilized water.
In an embodiment according to the invention, a procedure is used in which the polypeptide-containing solution is dialyzed against a buffer, for example a phosphate, tris-glycine, acetate or citrate buffer, having a concentration of 0.001 to 0.1 mol/1, preferably of 0.01 to 0.05 mol/1, having a pH of 2 to 10, preferably of 4 to N, containing at least one amino acid which can contain another amino group or a guanidino group, or an amino acid derivative, for example lysine, ornithine, arginine, diaminopimelic acid, agmatine, creatinine, guanidino-acetic acid, acetylornithine, citrulline, arginino-succinic acid, tranexamic acid or epsilon-aminocaproic acid, preferably lysine, ornithine or arginine in a concentration of 0.005 to 0.5 moll, preferably of 0.01 to 0.3 mol/1, at a temperature of 2 to 30°C, preferably of 4 to 15°C.
The conductivity of the dialysis solution is preferably 1 to 50 mSi (20°C), preferably 5 to 30 mSi (20°C). The osmoeality is 10 to 2000 mOsrnol, preferably 100 to 1000 mOsrnol .
After completion of the dialysis, the polypeptide-containing solution is adjusted to the desired final concentration by concentration or dilution. The solution is then sterile filtered, bottled and, if desired, lyophilized.
n The solutions according to 'the invention are equally sux~table for use in human and veterinary medicine. As solely physiologically tolerable substances are added, neither inflammation nor skin irritation or vascular damage occurs in the administration of the solutions according to the inventiono Using the preparation forms according to the invention, it is now possible by means of sc or im administration to achieve plasma concentrations of polypeptides which make possible both prophylaxis and therapym The examples illustrate the inventiono - 5 - ..
Example 1 Preparation of the protein solutions for sc and im administration 1. r-t-PA {RActilyse) was purchased from Boehr:Lnger Ingelheim.
2. Urokinase (UK) (RActosol) was obtained from Behringwerke.
3. F XIII (RFibrogammin) was obtained from Behringwerke.
4. Antithrombin IIT (AT III) {RKybernin) was obtained from Behringwerke.
5. r-Hirudin was prepared by the process of EP
0,316,650.
The object of the present invention was therefore to make available an agent containing a polypeptide, which is suitable for sc ox im administration.
This object is achieved according to the invention in that at least one amino acid, ox a salt, derivative or homolog of an amino acid, is incorporated in the poly-peptide-containing solution. Preferably, a D- or h-amino acid is incorporated.
It has surprisingly been shown that the addition of such 15. a substance drastically improves the bioavailability and tolerability of polypeptides administered sc or im and thus makes possible their sc ox im administration.
Substances suitable for the purpose according to the invention are, for example, lysine, ornithine, arginine, diaminopimelic acid, agmatine, creatinine, guanidino-acetic acid, acetylornithine, citxulline, arginino-succinic acid, tranexamic acid or epsilon-aminoca;proic acid. A feature common to them all is the presence of a basic group in the form of an amino or guanidino group.
A particularly suitable combination has proved to be arginine and lysine, preferably 0.001 to 1 mo~./1., par-ticulaxly preferably 0.01 to 0.5 moll. The bio-availaba.lity of polypeptides administered sc or im is distinctly increased by such an addition in compaxisan to ~0 a solution which contains the polypeptide and, if de-sired, customary additives such as stabilizers.
This favorable influence of these substances on the bio-availability and/or improvement in the tolerability could be observed particularly for t-PA (tissue plasminogen activator), a t-PA mutant, hirudin, urokinase, AT III
(antithrombin III), factor ~CIIT, EFO (erythropoietin), von Willebrand factor and PP4 (placenta protein 4). The activity of the proteins to which, according to the invewtion, the described substances were added is main-tained even after lyophilization and dissolving before administration in sterilized water.
In an embodiment according to the invention, a procedure is used in which the polypeptide-containing solution is dialyzed against a buffer, for example a phosphate, tris-glycine, acetate or citrate buffer, having a concentration of 0.001 to 0.1 mol/1, preferably of 0.01 to 0.05 mol/1, having a pH of 2 to 10, preferably of 4 to N, containing at least one amino acid which can contain another amino group or a guanidino group, or an amino acid derivative, for example lysine, ornithine, arginine, diaminopimelic acid, agmatine, creatinine, guanidino-acetic acid, acetylornithine, citrulline, arginino-succinic acid, tranexamic acid or epsilon-aminocaproic acid, preferably lysine, ornithine or arginine in a concentration of 0.005 to 0.5 moll, preferably of 0.01 to 0.3 mol/1, at a temperature of 2 to 30°C, preferably of 4 to 15°C.
The conductivity of the dialysis solution is preferably 1 to 50 mSi (20°C), preferably 5 to 30 mSi (20°C). The osmoeality is 10 to 2000 mOsrnol, preferably 100 to 1000 mOsrnol .
After completion of the dialysis, the polypeptide-containing solution is adjusted to the desired final concentration by concentration or dilution. The solution is then sterile filtered, bottled and, if desired, lyophilized.
n The solutions according to 'the invention are equally sux~table for use in human and veterinary medicine. As solely physiologically tolerable substances are added, neither inflammation nor skin irritation or vascular damage occurs in the administration of the solutions according to the inventiono Using the preparation forms according to the invention, it is now possible by means of sc or im administration to achieve plasma concentrations of polypeptides which make possible both prophylaxis and therapym The examples illustrate the inventiono - 5 - ..
Example 1 Preparation of the protein solutions for sc and im administration 1. r-t-PA {RActilyse) was purchased from Boehr:Lnger Ingelheim.
2. Urokinase (UK) (RActosol) was obtained from Behringwerke.
3. F XIII (RFibrogammin) was obtained from Behringwerke.
4. Antithrombin IIT (AT III) {RKybernin) was obtained from Behringwerke.
5. r-Hirudin was prepared by the process of EP
0,316,650.
6. r-t-PA mutant (I~o. 1) was prepared by the process of EP 0,227,462.
7. von Willebrand {vW) was prepared by the process of DE 3,04,354 (1 mg of vW corresponds to 100 U of vW
antigen).
antigen).
8. PP4 was prepared by the process of EP 0~123,307.
9. r-erythropoietin (EPO) was prepared by the process of EP 0,123,307 (1 mg of EPO corresponds to 80,000 U
of EPO antigen).
The proteins 1 to 4 were dissolved in distilled water.
The proteins 1 to 9 were then dialyzed against the following buffers (Table 1).
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After the dialysis, the solutions obtained are sterile filtered and frozen at -20°C until use.
E~cample 2 Each ml of the thawed solutions from Example 1 was administered sc and im (femoral biceps) in animals (rats ar rabbits). In the case of im administration, the total volume of 1 ml was divided between four types of in~ec-tion.
The animals were treated as follows:
Number of Animals Test Substance Dose Rats Rabbits per group r-t-PA 3.318.2 mg/kg 2 3 Urokinase 5 mg/kg 3 F XIII 10 mg/kg 3 AT III 10 mg/kg 3 r-Hirudin 14 mg/kg 3 r-t-PA-mutant 1.7 mg/kg 2 von Willebrand 300 U/kg 3 PP4 10 mg/kg 3 EPO 2000 U/kg 3 After 0, 15, 30, 60, 120, 180, 240 and 3~0 minutes (r-t-PA mutant) or 0, 30, 60, 120, 180, 240, 300, 360, 420 and X50 minutes (r-t-PA, hirudin, urokinase AT III, F XIII, von Willebrand, EPO, PP4), blood samples (+ citrate) were taken. The blood samples were then immediately centri-fuged and tho rcasuli~ing citrate plasma was frozen 'at -20°C until the determination. The plasma concentration of the tes~~ substance was measured as follows:
r-t-.P.~1 ELISA (Biapool, Sweden) Urokinase ELISA (Biapool, Sweden) F XIII: Activity test (Behringwerke) -a-Antithrombin III: ELISA (Behringwerke) r-Hirudin: ELISA (Behringwerke) r-t-PA mutant ELISA (Biopool Sweden) von Willebrand: ELISA (Stago, France) PP4: ELISA (Behringwerke) r-Erythropoietin: ELISA (Behringwerke) The data determined were represented graphically, as shown in >3'igures 1 and 2. The area under the curve (AUC) was then calculated. This value is an expression of the bioavailability and makes possible comparison between the different presentation forms. The data show that the administration of the solutions according to the inven-tion, with the exception of urokinase and hirudin ensures a distinctly better bioavailability, in particular in the case of sc administration.
Surprisingly, it has been found that the hemorrhages occurring on sc and im administration of hirudin and of urokinase at the administration site using the presenta-tion form according to the invention occur distinctly less than when 'these substances are administered in their customary presentation forms.
Number of animals with hemorrhages im sc Hirudin 0.05 M tris 3/3 2/3 0.1 M NaCl (1 animal died as a result of the hemor-rhages) FIirudin 0.2 M argir~in~ 0/9 0/3 0.2 M lysine pI~I !.5 Urokinase 0.05 M Iris 2/3 2/3 0.1 M NaCl I. Hioavailability of t~PA in the rat Buffer ~'yge of n AUC + Variation (~) Administration 1 im 2 358 10~
sc 2 36 13~
~
2 im 2 386 2~
v sc 2 53 1~~
f 3 im 2 756 2~
~
sc 2 423 3~
~
4 im 2 669 17$
sc 2 382 11~
~
5 im (all animals died) sc (all animals died) 7 im 2 184 18~
f sc 2 87 2~
~
8 im 2 600 4~
sc 2 320 12~
~
9 im 2 610 10~
sc 2 290 11~
t 11 _ II. Bioavailability of t-PA mutant in the rat Buffer AUC + Variation Type (~) of n Administration 1 im 2 113 ~ 2~
sc 2 13 ~ 20~
2 im 2 295 1 0.5~
sc 2 161 t 12~
3 im 2 1524 ~ 13~
sc 2 1119 f 14~
4 im 2 1414 ~ 2~
sc 2 12?? t 21~
5 im 2 32 5~
sc 2 34 * 10~
6 im (all animals died directly after administration) sc (all animals died directly after administration) ? im 2 30 ~ 12~
sc 2 39 f 9~
III. Bioavailability of antithro~oba.n III (rabbits) Buffer AUC -~ Variation Type of n Administration (~) 1 im 3 450,000 t 28 sc 3 5?,000 f 19 3 im 3 601, 000 :t :L5 sc 3 116,400 f :!8 IV. Bioavailability of ~' RIII (rab~i~ts) Buffer Type of n AUC -~ Variation Administration 1 im 3 228, 000 -1 25 sc 3 35,000 f 12 3 im 3 60,600 f 23 sc 3 62,000 t 20 V. Bioavailability of von Wil~.~~ranei factor (rab~i~s~
Buffer Type of n AUC °~ Variation Administration 1 im 3 231 ~ 14 sc 3 61 t 20 3 im 3 715 ~ 16 sc 3 12 t 14
of EPO antigen).
The proteins 1 to 4 were dissolved in distilled water.
The proteins 1 to 9 were then dialyzed against the following buffers (Table 1).
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.
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After the dialysis, the solutions obtained are sterile filtered and frozen at -20°C until use.
E~cample 2 Each ml of the thawed solutions from Example 1 was administered sc and im (femoral biceps) in animals (rats ar rabbits). In the case of im administration, the total volume of 1 ml was divided between four types of in~ec-tion.
The animals were treated as follows:
Number of Animals Test Substance Dose Rats Rabbits per group r-t-PA 3.318.2 mg/kg 2 3 Urokinase 5 mg/kg 3 F XIII 10 mg/kg 3 AT III 10 mg/kg 3 r-Hirudin 14 mg/kg 3 r-t-PA-mutant 1.7 mg/kg 2 von Willebrand 300 U/kg 3 PP4 10 mg/kg 3 EPO 2000 U/kg 3 After 0, 15, 30, 60, 120, 180, 240 and 3~0 minutes (r-t-PA mutant) or 0, 30, 60, 120, 180, 240, 300, 360, 420 and X50 minutes (r-t-PA, hirudin, urokinase AT III, F XIII, von Willebrand, EPO, PP4), blood samples (+ citrate) were taken. The blood samples were then immediately centri-fuged and tho rcasuli~ing citrate plasma was frozen 'at -20°C until the determination. The plasma concentration of the tes~~ substance was measured as follows:
r-t-.P.~1 ELISA (Biapool, Sweden) Urokinase ELISA (Biapool, Sweden) F XIII: Activity test (Behringwerke) -a-Antithrombin III: ELISA (Behringwerke) r-Hirudin: ELISA (Behringwerke) r-t-PA mutant ELISA (Biopool Sweden) von Willebrand: ELISA (Stago, France) PP4: ELISA (Behringwerke) r-Erythropoietin: ELISA (Behringwerke) The data determined were represented graphically, as shown in >3'igures 1 and 2. The area under the curve (AUC) was then calculated. This value is an expression of the bioavailability and makes possible comparison between the different presentation forms. The data show that the administration of the solutions according to the inven-tion, with the exception of urokinase and hirudin ensures a distinctly better bioavailability, in particular in the case of sc administration.
Surprisingly, it has been found that the hemorrhages occurring on sc and im administration of hirudin and of urokinase at the administration site using the presenta-tion form according to the invention occur distinctly less than when 'these substances are administered in their customary presentation forms.
Number of animals with hemorrhages im sc Hirudin 0.05 M tris 3/3 2/3 0.1 M NaCl (1 animal died as a result of the hemor-rhages) FIirudin 0.2 M argir~in~ 0/9 0/3 0.2 M lysine pI~I !.5 Urokinase 0.05 M Iris 2/3 2/3 0.1 M NaCl I. Hioavailability of t~PA in the rat Buffer ~'yge of n AUC + Variation (~) Administration 1 im 2 358 10~
sc 2 36 13~
~
2 im 2 386 2~
v sc 2 53 1~~
f 3 im 2 756 2~
~
sc 2 423 3~
~
4 im 2 669 17$
sc 2 382 11~
~
5 im (all animals died) sc (all animals died) 7 im 2 184 18~
f sc 2 87 2~
~
8 im 2 600 4~
sc 2 320 12~
~
9 im 2 610 10~
sc 2 290 11~
t 11 _ II. Bioavailability of t-PA mutant in the rat Buffer AUC + Variation Type (~) of n Administration 1 im 2 113 ~ 2~
sc 2 13 ~ 20~
2 im 2 295 1 0.5~
sc 2 161 t 12~
3 im 2 1524 ~ 13~
sc 2 1119 f 14~
4 im 2 1414 ~ 2~
sc 2 12?? t 21~
5 im 2 32 5~
sc 2 34 * 10~
6 im (all animals died directly after administration) sc (all animals died directly after administration) ? im 2 30 ~ 12~
sc 2 39 f 9~
III. Bioavailability of antithro~oba.n III (rabbits) Buffer AUC -~ Variation Type of n Administration (~) 1 im 3 450,000 t 28 sc 3 5?,000 f 19 3 im 3 601, 000 :t :L5 sc 3 116,400 f :!8 IV. Bioavailability of ~' RIII (rab~i~ts) Buffer Type of n AUC -~ Variation Administration 1 im 3 228, 000 -1 25 sc 3 35,000 f 12 3 im 3 60,600 f 23 sc 3 62,000 t 20 V. Bioavailability of von Wil~.~~ranei factor (rab~i~s~
Buffer Type of n AUC °~ Variation Administration 1 im 3 231 ~ 14 sc 3 61 t 20 3 im 3 715 ~ 16 sc 3 12 t 14
Claims (4)
1. A pharmaceutical composition for subcutaneous or intramuscular administration essentially consisting of erythropoietin, arginine and lysine in a buffered solution.
2. The composition as claimed in claim 1, wherein the arginine and lysine are incorporated in a concentration of 0.001 to 1 mol/1.
3. The composition as claimed in claim 1, wherein the arginine and lysine are incorporated in a concentration of 0.01 to 0.5 mol/1.
4. A process for the preparation of a pharmaceutical composition for subcutaneous or intramuscular administration which method consists of adding arginine and lysine to a buffered solution containing erythropoietin.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3939346.1 | 1989-11-29 | ||
| DE3939346A DE3939346A1 (en) | 1989-11-29 | 1989-11-29 | MEDICINES FOR SUBCUTANEOUS OR INTRAMUSCULAR APPLICATION CONTAINING POLYPEPTIDES |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2030988A1 CA2030988A1 (en) | 1991-05-30 |
| CA2030988C true CA2030988C (en) | 2004-11-16 |
Family
ID=6394356
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002030988A Expired - Lifetime CA2030988C (en) | 1989-11-29 | 1990-11-28 | Pharmaceutical for subcutaneous or intramuscular administration containing polypeptides |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5691312A (en) |
| EP (1) | EP0430200B1 (en) |
| JP (1) | JP3143470B2 (en) |
| KR (1) | KR910009246A (en) |
| AT (1) | ATE106746T1 (en) |
| AU (1) | AU657466B2 (en) |
| CA (1) | CA2030988C (en) |
| DE (2) | DE3939346A1 (en) |
| DK (1) | DK0430200T3 (en) |
| ES (1) | ES2057339T3 (en) |
| IE (1) | IE64080B1 (en) |
| PT (1) | PT96016B (en) |
Families Citing this family (25)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5364839A (en) * | 1990-06-18 | 1994-11-15 | Genetics Institute, Inc. | Osteoinductive pharmaceutical formulations |
| DE4126984A1 (en) * | 1991-08-15 | 1993-02-18 | Boehringer Mannheim Gmbh | PROCESS FOR THE MANUFACTURE OF HUMAN PROTEIN-CONTAINING, SUITABLE MEDICAMENTS FOR INFUSION OR INJECTION USE |
| SE9300105D0 (en) * | 1993-01-15 | 1993-01-15 | Kabi Pharmacia Ab | STABLE PROTEIN SOLUTION |
| EP0803255A4 (en) * | 1994-06-03 | 1999-06-30 | Tsumura & Co | Medicinal composition |
| US5770700A (en) * | 1996-01-25 | 1998-06-23 | Genetics Institute, Inc. | Liquid factor IX formulations |
| TW518219B (en) * | 1996-04-26 | 2003-01-21 | Chugai Pharmaceutical Co Ltd | Erythropoietin solution preparation |
| US20030190307A1 (en) * | 1996-12-24 | 2003-10-09 | Biogen, Inc. | Stable liquid interferon formulations |
| CA2275890C (en) * | 1996-12-24 | 2011-11-01 | Biogen, Inc. | Stable liquid interferon formulations |
| DE10149030A1 (en) * | 2001-10-05 | 2003-04-10 | Viscum Ag | Preparation of storage-stable medicaments containing recombinant carbohydrate-binding polypeptides, especially r-viscumin, useful e.g. as cytotoxic agent, comprises cooling, freezing, spray-drying or lyophilizing solution of pH more than 6 |
| PL370652A1 (en) | 2001-12-21 | 2005-05-30 | Novo Nordisk Health Care Ag | Liquid composition of factor vii polypeptides |
| JP4583762B2 (en) * | 2002-02-27 | 2010-11-17 | イミュネックス・コーポレーション | Polypeptide preparation |
| DK2283856T3 (en) | 2002-06-21 | 2017-11-20 | Novo Nordisk Healthcare Ag | Stabilized solid compositions of Factor VIIa polypeptides |
| US7897734B2 (en) | 2003-03-26 | 2011-03-01 | Novo Nordisk Healthcare Ag | Method for the production of proteins |
| ATE454900T1 (en) | 2003-05-23 | 2010-01-15 | Novo Nordisk Healthcare Ag | STABILIZATION OF PROTEINS IN SOLUTION |
| ES2574581T3 (en) | 2003-08-14 | 2016-06-20 | Novo Nordisk Health Care Ag | Aqueous liquid pharmaceutical composition of Factor VII polypeptides |
| SI2298287T1 (en) | 2003-12-19 | 2018-08-31 | Novo Nordisk Health Care Ag | Stabilised compositions of factor VII polypeptides |
| EP3673919A1 (en) | 2005-06-14 | 2020-07-01 | Amgen Inc. | Self-buffering protein formulations |
| US20090029147A1 (en) * | 2006-06-12 | 2009-01-29 | Aspen Aerogels, Inc. | Aerogel-foam composites |
| WO2009130181A2 (en) * | 2008-04-21 | 2009-10-29 | Novo Nordisk Health Care Ag | Dry transglutaminase composition |
| CN104080506B (en) | 2011-11-30 | 2017-03-08 | 3M创新有限公司 | Microneedle devices comprising peptide therapeutics and amino acids and methods of making and using same |
| SMT202300072T1 (en) | 2014-03-28 | 2023-05-12 | Univ Duke | Treating breast cancer using selective estrogen receptor modulators |
| BR112017023228A2 (en) | 2015-04-29 | 2018-11-06 | Radius Pharmaceuticals Inc | methods for cancer treatment |
| KR102413592B1 (en) | 2016-10-21 | 2022-06-27 | 암젠 인크 | Pharmaceutical formulations and methods of making the same |
| WO2018129419A1 (en) | 2017-01-05 | 2018-07-12 | Radius Pharmaceuticals, Inc. | Polymorphic forms of rad1901-2hcl |
| US11643385B2 (en) | 2018-07-04 | 2023-05-09 | Radius Pharmaceuticals, Inc. | Polymorphic forms of RAD1901-2HCl |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS56135418A (en) * | 1980-03-27 | 1981-10-22 | Green Cross Corp:The | Heat treatment of aqueous solution containing 8 factor of coagulation of blood derived from human |
| GB2079292A (en) | 1980-07-05 | 1982-01-20 | Speywood Lab Ltd | Blood Clotting Factor Production |
| US4508709A (en) * | 1983-12-05 | 1985-04-02 | Armour Pharmaceutical Company | Process for purifying factor VIII:C |
| EP0156169B1 (en) * | 1984-02-29 | 1991-12-18 | Asahi Kasei Kogyo Kabushiki Kaisha | An aqueous solution of a tissue plasminogen activator dissolved therein at an increased concentration and a method |
| US4656034A (en) * | 1985-05-20 | 1987-04-07 | Survival Technology, Inc. | Absorption enhancing agents |
| JPS6197229A (en) * | 1984-10-18 | 1986-05-15 | Chugai Pharmaceut Co Ltd | Stable erythropoietin preparation |
| US4839170A (en) * | 1985-10-01 | 1989-06-13 | Survival Technology, Inc. | Protein absorption enhancing agents |
| DE3625090A1 (en) * | 1986-07-24 | 1988-01-28 | Behringwerke Ag | AGENT FOR THE THERAPY FACTOR VIII-RESISTANT HAEMOPHILY A AND METHOD FOR THE PRODUCTION THEREOF |
| DE3643182A1 (en) * | 1986-12-18 | 1988-06-30 | Behringwerke Ag | MEDICINAL PRODUCTS CONTAINING THE TISSUE PROTEIN PP4, METHOD FOR THE PRODUCTION OF PP4 AND ITS PASTEURIZATION AND THE USE OF PP4 |
| US4857320A (en) | 1987-02-19 | 1989-08-15 | Monsanto Company | Method of enhancing the solubility of tissue plasminogen activator |
| DE3729863A1 (en) * | 1987-09-05 | 1989-03-16 | Boehringer Mannheim Gmbh | STABILIZED ERYTHROPOIETIN LYOPHILISATES |
| DE3718889A1 (en) * | 1987-06-05 | 1988-12-22 | Behringwerke Ag | METHOD FOR PRODUCING A SOLUTION OF HIGH SPECIFIC VOLUME ACTIVITY FROM A PROTEIN WITH TISSUE PLASMINOGEN ACTIVATOR (T-PA) ACTIVITY, SOLUTION, CONTAINING PROTEIN WITH T-PA ACTIVITY AND USE OF THE SOLUTION AND IN THE HUMAN VITALIZE |
| JP2708749B2 (en) * | 1987-08-10 | 1998-02-04 | エーザイ株式会社 | Injectable composition containing modified tPA |
| DE4126983A1 (en) * | 1991-08-15 | 1993-02-18 | Boehringer Mannheim Gmbh | METHOD FOR THE PRODUCTION OF HUMAN-PROTEIN-CONTAINING, PRESERVED MEDICAMENTS FOR INFUSION OR INJECTION USE |
| US5358708A (en) * | 1993-01-29 | 1994-10-25 | Schering Corporation | Stabilization of protein formulations |
-
1989
- 1989-11-29 DE DE3939346A patent/DE3939346A1/en not_active Withdrawn
-
1990
- 1990-11-27 KR KR1019900019250A patent/KR910009246A/en not_active Ceased
- 1990-11-28 ES ES90122730T patent/ES2057339T3/en not_active Expired - Lifetime
- 1990-11-28 IE IE429290A patent/IE64080B1/en not_active IP Right Cessation
- 1990-11-28 PT PT96016A patent/PT96016B/en not_active IP Right Cessation
- 1990-11-28 CA CA002030988A patent/CA2030988C/en not_active Expired - Lifetime
- 1990-11-28 EP EP90122730A patent/EP0430200B1/en not_active Expired - Lifetime
- 1990-11-28 DE DE59006032T patent/DE59006032D1/en not_active Expired - Lifetime
- 1990-11-28 JP JP02323438A patent/JP3143470B2/en not_active Expired - Lifetime
- 1990-11-28 AT AT90122730T patent/ATE106746T1/en not_active IP Right Cessation
- 1990-11-28 DK DK90122730.6T patent/DK0430200T3/en active
- 1990-11-28 AU AU67029/90A patent/AU657466B2/en not_active Expired
-
1995
- 1995-06-07 US US08/488,952 patent/US5691312A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| DE3939346A1 (en) | 1991-06-06 |
| DK0430200T3 (en) | 1994-09-26 |
| DE59006032D1 (en) | 1994-07-14 |
| ES2057339T3 (en) | 1994-10-16 |
| PT96016A (en) | 1991-09-13 |
| KR910009246A (en) | 1991-06-28 |
| IE64080B1 (en) | 1995-07-12 |
| JPH03170437A (en) | 1991-07-24 |
| EP0430200B1 (en) | 1994-06-08 |
| US5691312A (en) | 1997-11-25 |
| PT96016B (en) | 1998-06-30 |
| AU657466B2 (en) | 1995-03-16 |
| CA2030988A1 (en) | 1991-05-30 |
| ATE106746T1 (en) | 1994-06-15 |
| EP0430200A1 (en) | 1991-06-05 |
| JP3143470B2 (en) | 2001-03-07 |
| IE904292A1 (en) | 1991-06-05 |
| AU6702990A (en) | 1991-06-06 |
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